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Targeting Poly(I:C) to the TLR3-Independent Pathway Boosts Effector CD8 T Cell Differentiation through IFN-/β¹

Soo M. Ngoi^*, Michael G. Tovey and Anthony T. Vella^2,*

^* Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030; and Laboratory of Viral Oncology, Centre National de la Recherche Scientifique FRE2937, Institut Andre Lwoff, Villejuif, France

Poly(I:C) is an adjuvant used for antitumor treatment and vaccines because of its prominent effects on CD8 T cells and NK cells. Poly(I:C) binds TLR3 and this interaction is thought to be central for driving cell-mediated immune responses. We investigated the importance of TLR3 in poly(I:C)-mediated endogenous CD8 T cell responses using the pathogenic T cell stimulant Staphylococcus aureus enterotoxin A. While the responsive CD8 T cells expanded comparably in both wild-type and TLR3^–/– mice, differentiation of effector CD8 T cells was enhanced by poly(I:C) in the TLR3^–/– mice. A higher percentage of Ag-specific CD8 T cells became IFN- and TNF- producers in the absence of TLR3 signaling. Consistent with this boosted response was the observation that TLR3-deficient cells synthesized less IL-10 compared with TLR3-sufficient cells in response to poly(I:C). Ultimately, however, the fundamental mechanism of CD8 effector T cell differentiation through the TLR3-independent pathway was shown to be completely IFN-/β-dependent. Administration of IFN-/β-neutralizing Abs abolished the poly(I:C) effects in TLR3^–/– mice. These findings reveal specific roles of how dsRNA receptors shape CD8 T cell responses, which should be considered as poly(I:C) is authenticated as a therapeutic adjuvant used in vaccines.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants RO1 AI428585 and AI52108.

² Address correspondence and reprint requests to Dr. Anthony T. Vella, Department of Immunology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030. E-mail address: vella{at}uchc.edu

³ Abbreviations used in this paper: PAMP, pathogen-associated molecular patterns; BSS, balanced salt solution; CTM, MEM supplemented with L-glutamine, FCS, tumor cocktail; MDA5, melanoma differentiation-associated protein 5; RIG-I, retinoic acid-inducible gene I; SEA, staphylococcal enterotoxin A; TRIF, Toll/IL-1R domain-containing protein inducing IFN-β.